This application claims the benefit of U.S. Provisional Application Ser. No. 60/245,535, filed Nov. 2, 2000.
1. Field of the Invention
This invention relates to the treatment of cellular proliferative disorders, e.g., cancer, by administering to a patient (E)-2xe2x80x2-fluoromethylene-2xe2x80x2-deoxycytidine (xe2x80x9cfluoromethylenedeoxycytidinexe2x80x9d or xe2x80x9cFMdCxe2x80x9d), in combination with administering to the patient a platinate drug to increase the effectiveness of the treatment.
The following references are cited herein and are incorporated by reference in their entirety:
1. Sunkara et al., Synergistic antitumor activity of (E)-2xe2x80x2-fluoromethylene-2xe2x80x2-deoxycytidine (FMdC, MDL 101, 731), an inhibitor of ribonucleotide reductase in combination with S phase specific drugs. Proceedings of the 83 Annual Meeting of the American Association for Cancer Research, (March 1992) vol. 33, no. 3088, page 517;
2. Sunkara, European Patent EP 0 664 708;
3. Woessner., Richard D. et al., FMdC Antineoplastic Ribonucleotide-Diphosphate Reductase Inhibitor, Drugs of the Future (1999) 24(5):502-510.
2. State of the Art
(E)-2xe2x80x2-deoxy-2xe2x80x2-(fluoromethylene)cytidine (xe2x80x9cFMdCxe2x80x9d), a nucleoside analogue of deoxycytidine, is an anti-tumor agent. It has been shown to have effective cytotoxic activity against a wide variety of cancer tumor cells and has potent anti-tumor activity in a large number of xenograft models, including breast, prostate, lung, colon, stomach, pancreas, ovary, brain and hematopoietic cancers.
Once taken in by a cell, the FMdC prodrug is phosphorylated to yield FMdC di- and triphosphates. FMdC diphosphate irreversibly inhibits ribonucleotide reductase, resulting in a reduction in deoxyribonucleotide triphosphate (xe2x80x9cdNTPxe2x80x9d) pools. FMdC triphosphate competes with deoxycytidine triphosphate (xe2x80x9cdCTPxe2x80x9d) for incorporation into DNA, resulting in DNA chain termination and cell death. The combination of these two activities results in self-potentiation of the drug.
It has been demonstrated that FMdC as a single agent has potent in vitro cytotoxic activity against a wide variety of tumor cells as noted above. However, FMdC is effective (cytotoxic) only in cells undergoing active DNA synthesis. Thus, the greatest utility for FMdC in treating cancer may be in combination with agents that induce DNA synthesis by inducing DNA repair, e.g., DNA-damaging agents.
Platinates are cytotoxic drugs containing a core atom of platinum, including cisplatin, carboplatin and others. They are DNA-damaging agents and are used in the treatment of cancer because of their efficacy. Cisplatin (cis-diamminedichloroplatinum; cis-Pt(NH3)2Cl2; xe2x80x9cCDDPxe2x80x9d) is the best known example of this class of cytotoxic agents and has been used for many years in the treatment of solid tumors. However, the toxicity of these agents continues to be a major concern.
Accordingly, a need exists for an improved therapy for the treatment of cancer both to increase effectiveness and to decrease toxicity. It has been discovered that a treatment regimen of FMdC combined with a platinate (such as cisplatin as an example of the class) is effective in the treatment of cellular proliferative disorders (cancer).
This invention is directed to methods for treating cellular proliferative disorders. In particular, it is directed to a method for treating a cellular proliferative disorder in a patient by administering to the patient an effective amount of (E)-2xe2x80x2-deoxy-2xe2x80x2-(fluoromethylene)cytidine and administering to the patient an effective amount of a platinate, wherein the amounts of (E)-2xe2x80x2-deoxy-2xe2x80x2-(fluoromethylene)cytidine and platinate are selected to provide effective cellular proliferative disorder treatment.
In one embodiment, it is directed to a method for treating a cellular proliferative disorder in a patient comprising administering to the patient an effective amount of (E)-2xe2x80x2-deoxy-2xe2x80x2-(fluoromethylene)cytidine (FMdC); waiting a predetermined period; and administering to the patient an effective amount of a platinate. The amounts of (E)-2xe2x80x2-deoxy-2xe2x80x2-(fluoromethylene)cytidine and the platinate are selected to provide effective cellular proliferative disorder treatment.
In another embodiment, it is directed to a method for treating a cellular proliferative disorder in a patient comprising administering to the patient an effective amount of (E)-2xe2x80x2-deoxy-2xe2x80x2-(fluoromethylene)cytidine (FMdC); waiting until at least a portion of the FMdC has been taken up by a cell and phosphorlyated; and administering to the patient an effective amount of a platinate. The amounts of (E)-2xe2x80x2-deoxy-2xe2x80x2-(fluoromethylene)cytidine and cisplatin are selected to provide effective cellular proliferative disorder treatment.
In yet another embodiment, it is directed to a method for treating a cellular proliferative disorder in a patient comprising administering to the patient an effective amount of (E)-2xe2x80x2-deoxy-2xe2x80x2-(fluoromethylene)cytidine (FMdC); and administering to the patient an effective amount of cisplatin. The amounts of (E)-2xe2x80x2-deoxy-2xe2x80x2-(fluoromethylene)cytidine and cisplatin are selected to provide effective cellular proliferative disorder treatment.
The methods of this invention are used in the treatment of cellular proliferative disorders including lung cancer, breast cancer, prostate cancer, colon cancer, stomach cancer, pancreatic cancer, ovarian cancer, brain cancer, hematopoietic cancers, esophageal carcinoma, renal cell carcinoma, bladder cancer, head and neck cancer, leukemias, and sarcomas such as cholangiosarcoma and esophageal sarcoma.
The platinate is selected from cisplatin, carboplatin, oxaliplatin, ormaplatin, iproplatin, enloplatin, nedaplatin, ZD0473 (cis-amminedichloro(2-chloropyridine)platinum (II)), BBR3464 and the like. A preferred platinate is cisplatin.
Preferably, the FMdC is administered prior to the administration of the platinate. A predetermined period is selected between the administration of FMdC and the platinate. The predetermined time is 15 minutes to 24 hours. Preferably, it is from about 1 to 8 hours and more preferably it is about 4 hours.
In the methods of this invention, FMdC is administered in an amount from about 2 mg/m2 to about 800 mg/m2 body surface of the patient and the platinate, such as cisplatin, is administered from about 10 mg/m2 to about 150 mg/m2 body surface of the patient. FMdC may be administered either parenterally or orally and the platinate may be administered either parenterally or orally.